Project Summary As U.S. states decriminalize and legalize cannabis, its use is on the rise. Given the popular conception and some empirical evidence that cannabis users experience increased caloric intake during acute intoxication, there are concerns that higher rates of recreational marijuana use could exacerbate the current public health crisis of obesity and associated metabolic disease; chiefly type 2 diabetes. Paradoxically, however, cross sectional data demonstrate associations between chronic marijuana use and lower body mass index (BMI), prevalence of obesity, insulin resistance, and rates of type 2 diabetes, despite data supporting higher caloric intake acutely. Preliminary data from our lab suggest that different cannabinoids present in marijuana strains (e.g. ?9-tetrahydrocannabinol (THC) and cannabidiol (CBD)) render differential biologic effects on processes relevant to type 2 diabetes like insulin resistance via effects on inflammatory markers. Critically, there is huge diversity in the amounts and ratio of THC and CBD commercially available and widely used in states like Colorado and their impact on obesity processes is not known. Variations in the underlying inflammatory state that may result from the potency or constituent components of cannabis as it is now used likely relate to variability in insulin sensitivity, a critical biomarker of type 2 diabetes. We propose to carefully study the effects of cannabinoids on inflammatory cytokines and insulin sensitivity in cannabis users across the weight spectrum. Our global hypothesis is that the inflammatory effects of cannabis use vary as a function of the ratio of CBD to THC, and that inflammation may be a pathway by which cannabis influences insulin sensitivity and, thus, risk for type 2 diabetes. Data from this rigorously designed study may shed light on the cannabis use/metabolic disease paradox. The goal is to test the effects of three real world commercially-available cannabis strains that differ markedly in their ratio of CBD to THC. To that end, we will test the effects of three different cannabis products: a CBD product (14% CBD, 0% THC), a THC product (14% THC, 0% CBD), and a THC+CBD product (7% THC, 7% CBD) on inflammation and insulin sensitivity both acutely and chronically. We employ two observational designs: a study of acute effects with infrequent users who have been abstinent at least three months and a study of more sustained effects in cannabis users assigned to four weeks of use of one of three cannabis flower strains versus a matched control group who do not use cannabis. Blood levels of THC and CBD will be measured before, during, and after the exposure period in both cases, and associations between THC and CBD in blood and both inflammation and insulin sensitivity will be measured. Results from these studies will provide critical and timely data to the public and health professionals regarding the effects of cannabis use, including differential effects of various strains, on diabetogenic processes. These data are urgently needed in order to inform individual and policy level decisions in order to reduce the harm of cannabis use.